Process for the Preparation of Pyrimidine Compounds

ABSTRACT

A process for the preparation of a compound of Formula (I) and intermediates useful therein are provided. The process comprises reacting a compound of formula R 1 —CO—CH 2 -E with a compound of formula R 2 —CHX 1 X 2  in the presence of a compound of formula R 3 R 4 N—C(═NH)NH 2  and a catalyst, thereby to form a dihydropyrimidine; and oxidising the dihydropyrimidine to form the compound of Formula ( 1 ). R 1  is H or an alkyl group; R 2  is H, an alkyl or aryl group; R 3  and R 4  are each independently H, alkyl or aryl, or R 3  and R 4  are linked to form, together with the nitrogen to which they are attached to form a 5 to 7 membered heterocyclic ring; E is H, an unsubstituted alkyl group, and aryl group or an electron withdrawing group; and X 1  and X 2  are each independently leaving groups, or X 1  and X 2  together represent ═O.

The present invention concerns a process for the preparation ofpyrimidines and intermediate compounds useful in the preparationthereof.

Substituted pyrimidine compounds are valuable compounds for use inparticularly the pharmaceutical industry. Certain 2-aminopyrimidinecompounds are intermediates used in the preparation of pharmaceuticalcompounds useful in the treatment of, inter alia, hypercholesterolemia,hyperlipoproteinemia and artherosclerosis. Synthetic routes tosubstituted pyrimidine compounds have been disclosed in EP-A-0 521 471and WO01/04100. Nevertheless, it remains desirable to identifyalternative routes for the preparation of substituted pyrimidinecompounds.

According to a first aspect of the present invention, there is provideda process for the preparation of a compound of Formula (1):

which comprises

-   a) reacting a compound of formula R¹—CO—CH₂-E with a compound of    formula R²—CHX¹X² in the presence of a compound of formula    R³R⁴N—C(═NH)NH₂ and a catalyst, thereby to form a dihydropyrimidine;    and-   b) oxidising the dihydropyrimidine produced in step a) to form the    compound of Formula (1)    wherein-   R¹ is H or an alkyl group;-   R² is H or an alkyl or aryl group;-   R³ and R⁴ are each independently H, alkyl or aryl, or R³ and R⁴ are    linked to form, together with the nitrogen to which they are    attached, a 5 to 7 membered heterocyclic ring;-   E is H, an unsubstituted alkyl group, an aryl group or an electron    withdrawing group; and-   X¹ and X² are each independently leaving groups, or X¹ and X²    together represent ═O.

Dihydropyrimidines formed in step a) can be represented by the Formula(2):

It will be recognised that the compounds of Formula (2) can exist in anumber of tautomeric forms in which the double bonds are delocalisedinto other positions in the molecule, notably into different positionsaround the pyrimidine ring. Without wishing to be bound by any theory,it is believed that for certain compounds of Formula 2, the predominanttautomeric form is of Formula (2a):

Alkyl groups which may be represented by R¹ include linear, branched andcyclic alkyl groups commonly comprising from 1 to 8 carbon atoms.Preferred cyclic alkyl groups include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl groups. Preferred linear and branched alkylgroups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyland tert-butyl groups. Most preferably, R¹ represents isopropyl.

Alkyl groups which may be represented by R² are as described above forR¹.

Aryl groups which may be represented by R² include both homoaryl andheteroaryl groups, and commonly comprise at least one 5 to 7 memberedaromatic ring. Examples of aryl groups include phenyl, naphthyl andpyridyl groups. Most preferably, R² represents a phenyl group.

Alkyl and aryl groups which may be represented by R³ and R⁴ are asdescribed above for R¹ and R². In certain preferred embodiments, R³represents methyl and R⁴ represents H. In other preferred embodiments,both of R³ and R⁴ are H.

Alkyl and aryl groups which may be represented by R¹, R², R³ and R⁴ maybe unsubstituted or substituted by one or more substituents. Examples ofsubstituents include optionally substituted alkoxy (preferablyC₁₋₄-alkoxy), optionally substituted alkyl (preferably C₁₋₄-alkyl),optionally substituted aryl (preferably phenyl), optionally substitutedaryloxy (preferably phenoxy), optionally substituted heterocyclyl,polyalkylene oxide (preferably polyethylene oxide or polypropyleneoxide), carboxy, oxo, phosphato, sulpho, nitro, cyano, halo, especiallychloro and fluoro, ureido, —SO₂F, hydroxy, ester, —NR^(a)R^(b),—COR^(a), —CONR^(a)R^(b), —NHCOR^(a), carboxyester, sulphone, andSO₂NR^(a)R^(b) wherein R^(a) and R^(b) are each independently H,optionally substituted alkyl (especially C₁₋₄-alkyl) or optionallysubstituted aryl (preferably phenyl), or, in the case of —NR^(a)R^(b),—CONR^(a)R^(b) and —SO₂NR^(a)R^(b), R^(a) and R^(b) together with thenitrogen atom to which they are attached may represent an aliphatic oraromatic ring system. Optional substituents for any of the substituentsdescribed may be selected from the same list of substituents.

Unsubstituted alkyl groups which may be represented by E are thoseunsubstituted alkyl groups as described above for R¹.

Aryl groups which may be represented by E are as described above for R².

Electron withdrawing groups which may be represented by E include nitrogroups; nitrile groups; perhaloalkyl groups, such as trifluoromethyl andpentafluoroethyl; ester groups, especially alkyl carboxylate groups;sulphonamide groups; keto groups; amide groups; and aldehyde groups,especially formyl groups.

E may also represent a group of formula —CHX^(a)X^(b), wherein X^(a) andX^(b) each independently represents a halo, especially a chloro or bromogroup, an alkoxy group, especially a C₁₋₄alkoxy, such as a methoxy orethoxy group, an alkylthio group, especially a C₁₋₄alkylthio group, orX^(a) and X^(b) are linked to form a cyclic acetal or thioacetalcommonly comprising, with the carbon to which X^(a) and X^(b) arebonded, from 5 to 7 atoms in the ring. When E represents a group offormula —CHX^(a)X^(b), it is preferred that X^(a) is the same as X^(b).

Further groups which may be represented by E are groups of formula—CH₂E², wherein E² represents halo, especially bromo or chloro, or aphosphorus-containing moiety, such as a phosphate ester, for example offormula —OP(═O)(OR^(c))₂, a phosphonate ester, for example of formula—P(═O)(OR^(c))₂, a phosphite, for example of formula —P(OR^(c))₂, aphosphine, for example of formula —P(R^(c))₂, or a phosphine oxide, forexample of formula —P(═O)(R^(c))₂, in each of which R^(c) represents analkyl, such as a C₁₋₄ alkyl, or an aryl, such as a phenyl, group. WhenE² represents a phosphorus-containing moiety, it is preferably aphosphine oxide of formula —P(═O)(R^(d))₂ wherein Rd represents methyl,ethyl or phenyl.

E may also represent a group of formula —CR^(x)═CR^(y)R^(z), whereinR^(x), R^(y) and R^(z) each independently represent H, alkyl or aryl.Preferably, R^(x) and R^(y) represent H, and R^(z) represents anoptionally substituted C₁₋₅ alkyl chain. R^(z) is preferably substitutedby two hydroxy groups, commonly present as a protected 1,3-dihydroxymoiety. R^(z) preferably comprises a terminal carboxyl group, especiallya carboxy ester group. R^(z) is most preferably a group of formula:

-   -   wherein R^(t) is an alkyl group, preferably a tert-butyl group.

A particular compound of formula R¹—CO—CH₂-E is of formula:

-   -   wherein R^(t) is an alkyl group, preferably a tert-butyl group.

Preferably, E represents a group of formula —CO₂(C₁₋₄alkyl), andespecially —CO₂Me, —CO₂Et or —CO₂Pr.

Leaving groups which can be represented by X¹ and X² include chloro,bromo and iodo, especially chloro, groups, and alkoxy groups, especiallyC₁₋₄alkoxy, such as methoxy, groups. Commonly when X¹ and X² are leavinggroups, either both are selected from chloro, bromo or iodo, or both arealkoxy. It is most preferred that X¹ and X² together represent ═O.

Oxidising agents which may be employed in the process according to thepresent invention include those oxidising agents known in the art tooxidise dihydropyrimidines to pyrimidines. Examples of suitableoxidising agents include quinones, such as chloranil, and particularlysubstituted benzoquinones such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone; halogens, such as bromine,transition metal oxidants such as barium manganate, copper chloride,optionally in the presence of phenanthroline, and manganese dioxide;metallic oxidants, such as palladium on charcoal or other suitableplatinum group metals; and elemental sulfur. The most preferred oxidantsare elemental sulfur and manganese dioxide.

In certain embodiments of the present invention, particularly when Erepresents H or unsubstituted alkyl, and especially H, the product ofthe reaction obtained from step (a) is the substituted pyrimidine ratherthan a dihydropyrimidine. Without wishing to be bound by any theory, itis believed that any dihydropyrimidine formed is autoxidised to thepyrimidine by the presence of oxygen, or the dihydropyrimidineself-oxidises or disproportionates.

Preferred compounds of formula R¹—CO—CH₂-E are compounds of formula(C₁₋₄alkyl)-CO—CH₂CO₂R⁵, wherein R⁵ represents a C₁₋₄ alkyl group,especially a methyl, ethyl or isopropyl group. Most preferred compoundsof formula R¹—CO—CH₂-E are compounds of formulae:

Compounds of formula (CH₃)₂CH—CO—CH₂—CO₂—C₃H₇, preferably(CH₃)₂CH—CO—CH₂—CO₂—CH(CH₃)₂, form another aspect of the presentinvention. Such compounds may be prepared by methods analogous to thoseknown in the art for the preparation of similar compounds, such asmethyl isobutyrylacetate and ethyl isobutyrylacetate.

Preferred compounds of formula R²—CHX¹X² are compounds of formula:

wherein X³ represents a substituent, especially halo, and n is 0 or 1-5.Preferably X³ is chloro or fluoro, alkyl, preferably methyl, or alkoxy,preferably methoxy. Most preferably n is 1, and X³ is present at the4-position. Especially preferred is 4-fluorobenzaldehyde.

Preferred compounds of formula R³R⁴N—C(═NH)NH₂ are guanidine andmethylguanidine. The compounds of formula R³R⁴N—C(═NH)NH₂ can beemployed as the free base, but in many embodiments are advantageouslyemployed as a salt, such as a nitrate, carbonate or sulphate salt, andespecially a hydrochloride salt.

Preferred catalysts which can be employed in the present invention arebases.

Bases which can be employed in the process of the present invention arepreferably inorganic bases. Examples of inorganic bases include alkaliand alkaline earth metal carbonates and hydrogencarbonates, particularlysodium or potassium hydrogencarbonate and most preferably sodium orpotassium carbonate.

Step a) of the process according to the present invention preferablyemploys a solvent which is inert under the reaction conditions employed.In many embodiments, a polar solvent is employed, preferably a polaraprotic solvent, for example including dichloromethane,dimethylsulphoxide and tetrahydrofuran. Preferred solvents are amides,such as N-methylpyrrolidinone and especially dimethylformamide anddimethylacetamide. Mixtures of solvents may be employed if desired.

In many preferred embodiments of the present invention, a mixturecomprising the compound of formula R¹—CO—CH₂-E, compound of formulaR²—CHX¹X² and compound of formula R³R⁴N—C(═NH)NH₂ is formed, optionallyin the presence of a solvent, and the catalyst added to this mixture.

It will be recognised that the reaction conditions employed in Step a)of the present invention the process may be varied over a wide range,depending for example on the nature of the reagents and/or solventemployed. Step a) commonly employs a reaction temperature in the rangeof from about 50° C. to about 80° C., such as from about 55° to 65° C.In many embodiments, a mole ratio of compound of formula R³R⁴N—C(═NH)NH₂to compound of formula R¹—CO—CH₂-E of from about 1.5:1 to about 3.5:1,such as about 2 :1, can be advantageously employed. In many embodiments,a stoichiometric mole ratio, or a small molar excess, such as up toabout 1.2:1, of compound of formula R²—CHX¹X² to compound of formulaR¹—CO—CH₂-E is employed.

Step b) of the process preferably employs a solvent which is inert underthe reaction conditions employed. The solvent is selected according tothe nature of the oxidising agent employed, and may include the solventsdescribed above for step a). Further solvents which may be employed instep b) include non-polar solvents, for example hydrocarbons, such astoluene, and dialkylethers, such as methyl tertiary-butyl ether.Mixtures of solvents may be employed if desired.

It will be recognised that the reaction conditions employed in Step b)of the process according to the present invention may be varied over awide range, depending for example on the nature of the oxidant and/orsolvent employed. Step b) commonly employs a reaction temperature in therange of from about 50° C. to about 140° C., such as from about 100° C.to 120° C. In many embodiments, a stoichiometric mole ratio, or a molarexcess of oxidant to dihydropyrimidine is employed. In certain highlypreferred embodiments, the oxidant employed is MnO₂ and azeotropicconditions are employed, most preferably employing toluene as solvent,with a mole ratio of MnO₂ to dihydropyrimidine of from about 2:1 to 4:1being especially preferred.

Compounds of Formula (2) and tautomers thereof, especially compounds ofFormula (2a), wherein E is not H, R³ and R⁴ are not both unsubstitutedalkyl groups and R¹ is not —CH₃ when R² is unsubstituted phenyl oro-nitrophenyl are novel, and accordingly form a second aspect of thepresent invention. In such compounds, it is preferred that at least oneof R³ and R⁴ represents H, and that R² preferably represents a phenylgroup substituted by one or more halogens, and most preferablyrepresents a 4-fluorophenyl group.

Step a) of the process according to the first aspect of presentinvention forms a third aspect of the present invention.

Step b) of the process according to the first aspect of presentinvention forms a fourth aspect of the present invention.

When either or both of R³ and R⁴ is H, the compounds of Formulae (1) or(2) may be reacted with reagents to introduce a substituent onto theexocyclic nitrogen, especially to introduce an alkyl, especially amethyl, or an alkyl- or arylsulfonyl, especially a mesyl, substituent.

In a particularly preferred aspect of the present invention, there isprovided a process for the preparation of a compound of Formula (3):

which comprises

-   a) reacting a compound of formula R¹—CO—CH₂-E with a compound of    formula R²—CHX¹X² in the presence of a compound of formula    R⁷HN—C(═NH)NH₂ and a catalyst, thereby to form a dihydropyrimidine,    which may be represented by a compound of formula (2) or (2a) as    described above but in which R³ represents R⁷ and R⁴ is H;-   b) oxidising the dihydropyrimidine produced in step a) to form a    compound of Formula (4)    and-   c) reacting the compound of Formula (4) with a compound of formula    R⁶SO₂—X⁴ to give a compound of Formula (3);    wherein-   R¹, R²; E, X¹ and X² are as previously described;-   R⁶ represents alky or aryl, preferably methyl;-   R⁷ is H, alkyl or aryl; and-   X⁴ represents a leaving group, preferably Cl or Br.

Alkyl and aryl groups which may be represented by R⁷ are as describedabove for R³. In many embodiments, R⁷ represents H or a methyl group.

Preferred features for R¹, R²; E, X¹ and X² are as previously described.

The present invention is illustrated further, without limitation, by thefollowing examples.

EXAMPLE 1 Preparation of Methyl2-amino-4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-carboxylate

a) A 100 ml two neck round bottom flask equipped with a condenser andconnected to a nitrogen line was charged with p-fluorobenzaldehyde (0.57ml, 5 mmol), methyl isobutyrylacetate (“MIBA”, 0.79 g, 5.5 mmol),guanidine hydrochloride (1.19 g, 12.5 mmol), potassium carbonate (2.76g, 40 mmol) and 10 ml of anhydrous dimethylformamide (DMF). This mixturewas stirred and heated at 70° C. for 20 h. The reaction mixture changedfrom colourless to yellow during this time. After cooling, DMF wasremoved under vacuum and the residue partitioned between brine (50 ml)and ethyl acetate (200 ml). The aqueous phase was washed with ethylacetate (200 ml) and the combined organic layers were dried overmagnesium sulfate and filtered. The solvent was removed under vacuum toobtain 1 g of yellow solid. ¹HNMR and LC showed methyl2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6-dihydropyrimidine-5-carboxylateas the major component (82%).

¹H NMR (250 MHz, C₂D₆SO); δ 0.95-1.1 (2xd, 6H, CH(CH₃)₂), 3.45 (s, 3H,O—CH₃), 4.0 (septet, 1H, CH(CH₃)₂), 6.1 (broad s, 2H, NH₂), 7.1-7.3 (m,5-H, N—H & 4 C—H aromatic).

b) A 25 ml three neck round bottom flask evacuated and back-filled withnitrogen was charged with methyl2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6-dihydropyrimidine-5-carboxylate(100 mg) and 15 ml of anhydrous THF.2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (135 mg, 0.45 mmol) was addedunder nitrogen. The red solution was stirred at room temperature. After40 min, methyl2-amino-4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-carboxylate wasobserved by HPLC and LC-MS. The product was identified by comparisonwith a standard of high purity prepared by a different chemical route.Both samples co-eluted by HPLC and showed the same ions by positive andnegative electrospray mass spectrometry.

EXAMPLE 2 Preparation of Methyl2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6-dihydropyrimidine-5-carboxylate

Guanidine hydrochloride (12.1 g), 4-Fluorobenzaldehyde (7.0 g), methyl4-methyl-3-oxo-pentanoate (8.9 g) and DMF (150 ml) were charged to avessel equipped with a condenser and connected to a nitrogen line. Theresultant mixture was stirred until a clear solution was obtained.Potassium carbonate (17.5 g) is charged and the mixture heated to 70° C.for 3 hours. The reaction mixture was cooled to ambient temperature andfiltered. It contained methyl2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6-dihydropyrimidine-5-carboxylatein 55% yield. An analytical sample was prepared by removing the reactionsolvents by evaporation under reduced pressure, precipitating theproduct from the resultant oil in acetonitrlie and recrystallisationfrom acetonitrile.

¹H NMR (250 MHz, C₂D₆SO); δ 0.95-1.1 (2xd, 6H, CH(CH₃)₂), 3.45 (s, 3H,O—CH₃), 4.0 (septet, 1H, CH(CH₃)₂), 6.1 (broad s, 2H, NH₂), 7.1-7.3 (m,5-H, N—H & 4 C—H aromatic).

EXAMPLE 3 Preparation of Ethyl2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6-dihydropyrimidine-5-carboxylate

Guanidine hydrochloride (24.1 g), 4-Fluorobenzaldehyde (13.9 g), ethyl4-methyl-3-oxo-pentanoate (16.2 g) and DMF (300 ml) were charged to avessel equipped with a condenser and connected to a nitrogen line. Theresultant mixture was stirred until a clear solution was obtained.Sodium carbonate (26.8 g) was charged and the mixture heated to 70° C.for 4 hours. The reaction mixture contained ethyl2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6-dihydropyrimidine-5-carboxylatein 75% yield. DMF was removed by evaporation under reduced pressureuntil the reaction mixture contained 35-40% DMF by weight. Toluene wascharged (112 ml) and the temperature adjusted to 55° C. This solutionwas washed 3 times with 10% aqueous sodium chloride solution, cooled to10° C., washed with toluene (32 ml) and dried in a vacuum oven at 50° C.

¹H NMR (250 MHz, C₂D₆SO); δ 1.0 (t, 3H, CH₂CH₃), 1.1 (d, 6H, CH(CH₃)₂),3.9 (q, 2H, CH₂CH₃), 4.05 (septet, 1H, CH(CH₃)₂), 5.2 (s, 1H, N—C—H),6.1 (broad s, 2H, NH₂), 7.1 (t, 2H, C—H aromatic), 7.15-7.3 (m, 3H, N—H& 2 C—H aromatic).

EXAMPLE 4 Preparation of Isopropyl 4-methyl-3-oxo-pentanoate

Methyl 4-methyl-3-oxo-pentanoate (304 g), isopropyl alcohol (500 ml) andp-toluenesulfonic acid (3.8 g) were stirred together and heated toreflux at 90° C. After 3 hours, 400 ml of solvent was collected bydistillation at atmospheric pressure. Fresh isopropyl alcohol was addedand the mixture refluxed for a further 3 hours. The cycle ofdistillation, addition of fresh solvent and refluxing was continueduntil the conversion had reached 95%, determined by a peak area ratio ofproduct:starting material of 95:5 measured by LC. The remaining volatilesolvents were removed by distillation and the resultant liquid washedwith 10% sodium carbonate solution and dried over anhydrous sodiumsulfate and filtered to give isopropyl 4-methyl-3-oxo-pentanoate as aclear liquid (301 g, 83%).

¹H NMR (250 MHz, C₂D₆SO); δ 1.05, 1.2 (2xd, 12H, C—CH(CH₃)₂,O—CH(CH₃)₂), 2.7 (septet, 1H, C—CH(CH₃)₂), 3.6 (s, 2H, CH₂), 4.05(septet, 1H, O—CH(CH₃)₂).

EXAMPLE 5 Preparation of Isopropyl2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6-dihydropyrimidine-5-carboxylate

Guanidine hydrochloride (12.1 g), 4-Fluorobenzaldehyde (7.0 g),isopropyl 4-methyl-3-oxo-pentanoate (8.9 g) and DMF (150 ml) werecharged to a vessel equipped with a condenser and connected to anitrogen line. The resultant mixture was stirred until a clear solutionwas obtained. Potassium carbonate (17.5 g) was charged and the mixtureheated to 70° C. for 3 hours. The reaction mixture was cooled to ambienttemperature, filtered, and the solvents removed by evaporation underreduced pressure. The resultant oil was triturated in water at 80° C.and cooled to give a slurry that was filtered and dried to giveisopropyl2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6-dihydropyrimidine-5-carboxylatein 67% yield.

¹H NMR (250 MHz, C₂D₆SO); δ 0.9-1.15 (d, 12H, C—CH(CH₃)₂, O—CH(CH₃)₂),4.0 (septet, 1H, C—CH(CH₃)₂), 4.75 (septet, 1H, O—CH(CH₃)₂), 5.2 (s, 1H,N—C—H), 6.1 (broad s, 2H, NH₂), 7.1 (t, 2H, C—H aromatic), 7.2 (m, 3H,N—H & 2 C—H aromatic).

EXAMPLE 6 Preparation of Ethyl4-(4-fluorophenyl)-6-isopropyl-2-methylamino-1,6-dihydropyrimidine-5-carboxylate

1-Methylguanidine hydrochloride (8.25 g), 4-Fluorobenzaldehyde (4.2 g),ethyl 4-methyl-3-oxo-pentanoate (5.0 g) and DMF (100 ml) were charged toa vessel equipped with a condenser and connected to a nitrogen line. Theresultant mixture stirred until a clear solution is obtained. Sodiumcarbonate (4.0 g) was charged and the mixture heated to 70° C. for 2hours. The reaction mixture was cooled to ambient temperature, filtered,and the solvents removed by evaporation under reduced pressure. Theresultant oil was triturated in water at 50° C. and cooled to give aslurry that was filtered and dried to give ethyl4-(4-fluorophenyl)-6-isopropyl-2-methylamino-1,6-dihydropyrimidine-5-carboxylatein 63% yield.

¹H NMR (250 MHz, C₂D₆SO); δ 0.95-1.1 (m, 9H, CH₂CH₃ & CH(CH₃)₂), 2.7 (s,3H, NH—CH₃), 3.9 (q, 2H, CH₂CH₃), 4.0 (septet, 1H, CH(CH₃)₂), 5.2 (s,1H, N—C—H), 6.4 (broad s, 1H, NH—CH₃), 7.1 (t, 2H, C—H aromatic), 7.2(m, 3H, N—H & 2 C—H aromatic).

EXAMPLE 7 Preparation of Methyl4-(4-fluorophenyl)-6-isopropyl-2-(1-pyrazolyl)-1,6-dihydropyrimidine-5-carboxylate

1H-Pyrazole carboxamidine (prepared according to the method ofBernatowicz, Wu and Matsueda; J. Org. Chem., 52, 2497-2502, 1992; 0.91g), 4-Fluorobenzaldehyde (0.37 g), methyl 4-methyl-3-oxo-pentanoate (0.4g), potassium carbonate (1.38 g) and DMF (10 ml) were charged to a smallvessel. The resultant mixture was heated to 85° C. for 6 hours. Thereaction mixture was cooled to ambient temperature, filtered, and thesolvents removed by evaporation under reduced pressure. The resultantoil was triturated in water to give a slurry that was filtered, washedand dried. The major component isolated by column chromatography wasMethyl4-(4-fluorophenyl)-6-isopropyl-2-(1-pyrazolyl)-1,6-dihydropyrimidine-5-carboxylate.

¹H NMR (250 MHz, C₂D₆SO); δ 1.05-1.2 (2xd, 6H, CH(CH₃)₂), 3.55 (s, 3H,O—CH₃), 4.0 (septet, 1H, CH(CH₃)₂), 5.5 (s, 1H, N—C—H), 6.55 (m, 1H,pyrazolyl C—H), 7.0 (t, 2H, phenyl C—H), 7.3 (m, 3H, N—H & 2 phenylC—H), 7.7 (m, 1H, pyrazolyl C—H), 8.4 (m, 1H, pyrazolyl C—H).

EXAMPLE 8 Preparation of2-amino-4-(4-fluorophenyl)-6-isopropyl-pyrimidine

Guanidine hydrochloride (1.19 g), 4-Fluorobenzaldehyde (0.62 g),3-methyl butan-2-one (0.47 g) and DMF (20 ml) were charged to a flask.The resultant mixture was stirred until a clear solution was obtained.Sodium tert-butoxide (2.36 g) was charged and the mixture stirred atambient temperature for 18 hours. The reaction mixture contained2-amino-4-(4-fluorophenyl)-6-isopropyl-pyrimidine in 30% yield. Themajor component was isolated by flash column chromatography on silica,eluting with ethyl acetate/hexanes (1:4).

¹H NMR (250 MHz, CDCl₃); δ 1.25 (d, 6H, CH(CH₃)₂), 2.8 (septet, 1H,CH(CH₃)₂), 6.6 (broad s, 2H, NH₂), 7.35 (t, 2H, C—H aromatic), 8.15 (m,2 C—H aromatic).

EXAMPLE 9 Preparation of Ethyl2-amino-4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-carboxylate

Ethyl2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6-dihydropyrimidine-5-carboxylate(22.6 g) was dissolved in toluene (150 ml) and heated until a solutionwas obtained. Manganese dioxide (18.8 g) was added as a slurry intoluene (150 ml) and the mixture refluxed under azeotropic conditionsfor 6 hours until conversion was complete. A small amount of water wascollected in the Dean and Stark trap. The slurry was filtered and thesolvents removed by evaporation under reduced pressure to give ethyl2-amino-4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-carboxylate as acrystalline solid in 96% yield.

¹H NMR (250 MHz, C₂D₆SO); δ 0.95 (t, 3H, CH₂CH₃), 1.2 (d, 6H, CH(CH₃)₂),3.1 (septet, 1H, CH(CH₃)₂), 4.05 (q, 2H, CH₂CH₃), 7.1 (broad s, 2H,NH₂), 7.3 (t, 2H, C—H aromatic), 7.55 (m, 2 C—H aromatic).

EXAMPLE 10 Preparation of Ethyl2-amino-4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-carboxylate

The process of Example 9 was repeated, but using elemental sulfur (4.7g) in place of the manganese dioxide, and a reaction time of 24 hours.The product was obtained in a near quantitative conversion.

EXAMPLE 11 Preparation of Ethyl4-(4-fluorophenyl)-6-isopropyl-2-methylamino-pyrimidine-5-carboxylate

The process of Example 9 was repeated but employing 10 mmol of ethyl4-(4-fluorophenyl)-6-isopropyl-2-methylamino-1,6-dihydropyrimidine-5-carboxylatein place of ethyl2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6-dihydropyrimidine-5-carboxylate,with the other reagents and components reduced proportionately. Theproduct was obtained in a near quantitative conversion.

¹H NMR (250 MHz, C₂D₆SO); δ 0.95 (t, 3H, CH₂CH₃), 1.2 (d, 6H, CH(CH₃)₂),2.85 (d, 3H, N—CH₃), 3.1 (septet, 1H, CH(CH₃)₂), 4.05 (q, 2H, CH₂CH₃),7.3 (t, 2H, C—H aromatic), 7.45-7.65 (broad s, 3-H, N—H & 2 C—Haromatic).

1. A process for the preparation of a compound of Formula (1):

which comprises a) reacting a compound of formula R¹—CO—CH₂-E with acompound of formula R²—CHX¹X² in the presence of a compound of formulaR³R⁴N—C(═NH)NH₂ and a catalyst, thereby forming a dihydropyrimidine; andb) oxidising the dihydropyrimidine produced in sea) to form the compoundof Formula (1) wherein R¹ is H or an alkyl group; R² is H, an alkyl, oraryl group; R³ and R⁴ are each independently H, alkyl, or aryl; or R³and R⁴ are linked to form, together with the nitrogen to which they areattached, a 5 to 7 membered heterocyclic ring; E is H, an unsubstitutedalkyl group, an aryl groups or an electron withdrawing group; and X¹ andX² are each independently leaving groups; or X¹ and X² together ═O.
 2. Aprocess according to claim 1, wherein the dihydropyrimidine isrepresented by the Formula (2a), and tautomers thereof:


3. A process according to claim 1, wherein the compound of formulaR¹—CO—CH₂-E is a compound of formula:


4. A process according to claim 1, wherein the compound of formulaR²—CHX¹X² is a compound of formula:

wherein X³ is halo, and n is 0 or 1-5.
 5. A process according to claim1, wherein the compound of formula R³R⁴N—C(═NH)NH₂ is guanidine ormethylguanidine.
 6. A process according to claim 5, wherein the compoundof formula R³R⁴N—C(═NH)NH₂ is employed as a hydrochloride or sulfatesalt.
 7. A process according to claim 1, wherein the catalyst is a base.8. A process according to claim 7, wherein the base is an alkali oralkaline earth metal carbonate or hydrogencarbonate.
 9. A processaccording to claim 1, wherein the oxidising agent is manganese dioxide.10. A compound of Formula (2a), and tautomers thereof:

wherein R is H or an alkyl group; R² is H, an alkyl or aryl group; R³and R⁴ are each independently H, alkyl, or aryl; provided that R³ and R⁴are not both unsubstituted alkyl; and E is an unsubstituted alkyl group,an aryl groups or an electron withdrawing group; further provided thatR¹ is not —CH₃ when R² is unsubstituted phenyl or o-nitrophenyl.
 11. Acompound according to claim 10, wherein R² is a phenyl group substitutedwith one or more halogens.
 12. A compound according to claim 10, whereinat least one of R³ and R⁴ is H.
 13. A compound according to claim 10,wherein R¹ is isopropyl and R² is 4-fluorophenyl.
 14. A compoundaccording to claim 10, wherein R³ is H or methyl and R⁴ is H.
 15. Acompound according to claim 10, wherein E is a group of formula—CO₂(C₁₋₄alkyl).
 16. A process for the preparation of a compound ofFormula (2a) and tautomers thereof:

which comprises a) reacting a compound of formula R¹—CO—CH₂-E with acompound of formula R²—CHX¹X² in the presence of a compound of formulaR³R⁴N—C(═NH)NH₂ and a catalyst, thereby forming the compound of Formula(2a) wherein R¹ is an H or an alkyl group; R² is an H, an alkyl, or arylgroup; R³ and R⁴ are each independently H, alkyl or aryl; or R³ and R⁴are linked to form, together with the nitrogen to which they areattached, a 5 to 7 membered heterocyclic ring; E is H, an unsubstitutedalkyl group, an aryl groups or an electron withdrawing group; and X¹ andX² are each independently leaving groups; or X¹ and X² together are ═O.17. A process according to claim 16, wherein R¹ is isopropyl, R² isR⁴-fluorophenyl, and R³ and R⁴ are each independently represents H ormethyl.
 18. A process according to claim 17, wherein R³ is methyl and R⁴is H.
 19. A process for the preparation of a compound of Formula (1):

which comprises oxidising a compound of Formula (2a):

wherein R¹ is H or an alkyl group; R² is an H, an alkyl or aryl group;R³ and R⁴ are each independently H, alkyl, or aryl; or R³ and R⁴ arelinked to form, together with the nitrogen to which they are attached, a5 to 7 membered heterocyclic ring; and E is H, an unsubstituted alkylgroup, an aryl group, or an electron withdrawing group.
 20. A processaccording to claim 19, wherein R¹ is isopropyl, R² is 4-fluorophenyl,and R³ and R⁴ are each independently H or methyl.
 21. A processaccording to claim 19, wherein the oxidation employs manganese dioxide.22. A process for the preparation of a compound of Formula (3):

which comprises a) reacting a compound of formula R¹—CO—CH₂-E with acompound of formula R²—CHX¹X² in the presence of a compound of formulaR⁷HN—C(═NH)NH₂ and a catalyst, thereby forming a dihydropyrimidine; b)oxidising the dihydropyrimidine produced in a) to form a compound ofFormula (4)

and c) reacting the compound of Formula (4) with a compound of formulaR⁶SO₂—X⁴ to give a compound of Formula (3); wherein R¹ is H or an alkylgroup; R² is H, an alkyl, or aryl group; E is H, an unsubstituted alkylgroup, an aryl group, or an electron withdrawing group; X¹ and X² areeach independently leaving groups; or X¹ and X² together are ═O; R⁶alkyl or aryl; R⁷ is H, alkyl or aryl; and X⁴ is a leaving group.
 23. Aprocess for the preparation of a compound of Formula (3):

which comprises a) reacting a compound of formula R¹—CO—CH₂-E with acompound of formula R²—CHX¹X² in the presence of a compound of formulaR⁷HN—C(═NH)NH₂ and a catalyst, thereby t forming a dihydropyrimidinecomprising an exocyclic group formula —NHR⁷; b) reacting a compound ofFormula (4)

with a compound of formula R⁶SO₂—X⁴ to form a dihydropyrimidinecomprising an exocyclic group formula —N(R⁷)SO₂R⁶; c) oxidising thedihydropyrimidine produced in b) to form a compound of Formula (3);wherein R¹ is H or an alkyl group; R² is H, an alkyl or aryl group; E isH, an unsubstituted alkyl group, an aryl group, or an electronwithdrawing group; X¹ and X² are each independently leaving groups; orX¹ and X² together are ═O; R⁶ is alkyl or aryl; R⁷ is H, alkyl or aryl;and X⁴ is a leaving group.
 24. A process according to claim 22, whereinR¹ is isopropyl, R² is 4-fluorophenyl, X¹ and X² together are ═O, R⁶ ismethyl, E is a group of formula —CO₂(C₁₋₄alkyl), and R⁷ is H or methyl.25. A compound of formula (CH₃)₂CH—CO—CH₂—CO₂—C₃H₇.
 26. A compoundaccording to claim 25, of formula: